Daily oscillations in many biological processes that are controlled through an endogenous circadian clock occur during a 24-hour period. This clock measures changes in light and mediates photoperiodic responses. Previous research indicated that circadian rhythms could control the activity of the cell cycle, but only now has work by Hitoshi Okamura and colleagues indicated that the underlying mechanism involves direct transcriptional regulation of the cell-cycle gene Wee1 by Clock — a master control switch of circadian gene expression.

Using a mouse model with a partial hepatectomy (PH), Okamura and colleagues analysed the relationship between the circadian clock and the cell cycle. Liver cells from wild-type mice that have undergone a PH rapidly re-enter the cell cycle and repopulate the liver in a few days. The rate of liver regrowth was studied in mice that were maintained in a 12-hour light/dark cycle, with a PH on the liver performed at the start of the 12-hour light period (ZT0) or 8 hours later (ZT8). The results of bromodeoxyuridine (BrdU) incorporation, which marks cell proliferation, indicated that although S-phase kinetics were similar for both ZT0 and ZT8, there was a delay in cells entering mitosis if the PH was performed at ZT0. This indicates that the timing of the hepatectomy affects cell-cycle progression in the regenerating cells. Peaks of the cell-cycle protein kinase Cdc2 and messenger RNA levels of other cell-cycle regulators, including Wee1 — which is a known Cdc2 regulator — mimicked the BrdU incorporation peaks, which pointed to the involvement of cell-cycle regulators in this process.

Performing a PH on mice that are mutant for known clock regulators, such as the blue-light sensitive photoreceptor cryptochromes (cry), prevented normal liver regeneration and inhibited the peak of Cdc2 activity. Levels of Wee1 were increased in cry-mutant mice, but decreased in clock-mutant mice. Clock regulates gene expression by binding E-box motifs and three of these were identified in the 5′ UTR of Wee1. When these regions are mutated, transcription of Wee1 by Clock/Bmal1 is decreased, presumably because Clock no longer binds upstream of Wee1 to regulate its transcription. This indicates a direct but unidirectional regulatory mechanism (the authors show that there is no feedback) between the circadian clock and cell-cycle regulation.

As the molecular mechanisms that underlie the action of the circadian clock are still poorly understood, further genetic analysis of the links between cell-cycle regulators and clock components should provide important clues to the control of this regulatory mechanism.